Process for producing imidazole derivative

ABSTRACT

The present invention is directed to a process for preparing the following compound ##STR1## which is prepared starting from ##STR2## which is reacted succesively with 4-iodobenzyl or 4-bromobenzyl bromide, hydrazine and 1,4-dimethyl-1,3-cyclohexadiene, reduced and reacted with phenyltetrazole or suitably protected phenyltetrazole followed by removal

This application is the national phase of international applicationPCT/US94/06028, filed Jun. 21, 1993 which claims the priorty of JapaneseApplication No. 149132/1993, filed Jun. 21, 1993.

BACKGROUND

Industrial Field of Utilization

The present invention relates to a process for producing an imidazolederivative. More particularly, it relates to a process for producing animidazole derivative represented by the chemical formula [I]: ##STR3##which is useful for hypertension, congestive heart failure, renalfailure, glaucoma, hyperuricemia and the like, in which complicatedsteps are avoided.

The above compound is an angiotensin II antagonist and is thus useful asan agent for preventing or treating hypertension, congestive heartfailure, renal failure, glaucoma, hyperuricemia and the like. Thepresent inventors have found that drugs of this class have longer shelflife, higher activity, rapid manifestation of action upon intravenousinjection, good absorbability into the body upon oral administration,lower toxicity and long-lasting action. These novel compounds areimidazole derivatives having the hydrazine cross-linking structurerepresented by the formula: ##STR4## as described in Japanese PatentApplication No. 3-277537, No. 3-323474, No. 4-095191 and No. 4-216809and published PCT application WO 93/08193, published Apr. 29, 1993,which claims the benefit thereof. In the above applications, we reportedthe imidazole derivative [I] represented by the chemical formula:##STR5## had particularly good effects. And we disclosed, in the abovepatent applications and Japanese Patent Application No. 5-060067, thatthis imidazole derivative can be synthesized according to the followingroute (Reaction scheme 1). In the route, a compound (1) is firstprotected with benzyl group, and after a few steps, the protectedcompound is debenzylated by hydrogenolysis to give a compound (4) andthereafter, a biphenyltetrazole part is linked thereto to give an endcompound [I]. However, the above route has the problems in productionefficacy and economical properties. In this regard, Richard F. Shuman etal. reported an improved process for producing biphenyltetrazoles whichare an intermediate useful for production of angiotensin II antagonistin U.S. Pat. No. 5,039,814. ##STR6##

INFORMATION DISCLOSURE

Methods of synthesis of compounds of the formula I are described in WO93/08193, published Apr. 29, 1993. Another process is discussed in U.S.Pat. No. 5,039,814.

SUMMARY OF THE INVENTION

Problems to be Solved by the Invention

The object of the present invention is to provide a process forproducing an imidazole derivative having the excellent effects withoutpassing through the complicated synthesis route.

The present inventors have studied the problems and have found that theimidazole compound can be prepared without passing through a reaction ofdeprotecting the benzyl group by introducing therein a p-halogenobenzylgroup, which resulted in completion of the present invention.

That is, the present invention provides a process for producing an endcompound [I] (Process A) which comprises introducing p-halogenobenzylgroup in the compound (1) in place of protecting the compound (1) withbenzyl group, subjecting the protected compound to the following route(Reaction Scheme 2) to give a compound (8), subjecting the resultingcompound to cross-coupling with phenyltetrazole or suitably protectedphenyltetrazole to construct a biphenyltetrazole part, and subjectingthe resulting compound to diisobutylaluminium hydride (DIBAH) reduction,and a process for producing an end compound [I] (Process B) whichcomprises subjecting a compound (8) to diisobutylaluminium hydridereduction to give a compound (9), subjecting it to cross-coupling withphenyltetrazole or suitably protected phenyltetrazole to construct abiphenyltetrazole part. These processes do not need the complicatedprocedures such as protection with benzyl group, deprotection, synthesisof biphenyltetrazole, reaction with imidazole and the like. Furtherthese processes have the advantages such that all the reactions areutilized effectively for construction of an end compound and respectivesteps have the higher yield. ##STR7##

As the alkyl group represented by a variable substituent R, there aremethoxymethyl, methoxyethoxymethyl, trimethylsilylethoxymethyl and thelike. As the optionally substituted aryl group, there are benzyl,diphenylmethyl, triphenylmethyl, naphthylmethyl, 9-anthrylmethyl and thelike, said aryl being optionally substituted with lower alkyl group suchas methyl, ethyl and the like or lower alkoxy group such as methoxy,ethoxy and the like.

Regarding the cross-coupling reaction used in the present invention,there is known a process for production of2-substituted-1-(tetrazol-5-yl)benzenes disclosed in U.S. Pat. No.5039814 (Reaction Scheme 3). However, this disclosure relates to aprocess for production of an intermediate (12) which is abiphenyltetrazole part and reports as R group on phenyltetrazole (11)only hydrogen and triphenylmethyl group. Therefore, one could not expectthat a reaction proceeds in the higher yield and selectively also in acompound having the complicated structure and higher reactive carbonylgroup and the like in the present invention. ##STR8##

As an inert solvent used in the present invention, any solvent can beused which has no adverse influence on a reaction, for example, DMF,dichloromethane, tetrahydrofuran and the like. The reaction is shown inReaction Scheme 2. A compound (1) is first dissolved in a suitablesolvent such as DMF and the like, the solution is, for example, reactedwith 4 -halogenobenzyl bromide in the presence of an base such as sodiumhydride and the like, ant the reaction is heated at refluxing withhydrazine monohydrate to give a compound (6). The compound (6) is thendissolved in a suitable solvent such as dichloromethane and the like,the solution is, for example, reacted with1,4-dimethyl-1,3-cyclohexanediene in the presence of an oxidizing agentsuch as lead tetraacetate and the like to give a compound (7). C ringdouble bond of the compound (7) is then reduced with a diimide generatedby dropping sodium acetate while heating at reflux in the presence ofp-toluenesulfonylhydrazine and dimethoxymethane to give a compound (8).Further, for example, phenyltetrazole (10) protected with a suitableprotecting group such as triphenylmethyl group and the like is dissolvedin a suitable solvent such as tetrahydrofuran and the like, the solutionis reacted with n-butyl lithium under cooling and further zinc chlorideis added thereto to give arylzinc chloride. This arylzinc chloride isreacted with the compound (8) in the presence of nickel to construct abiphenyltetrazole part. The resulting compound is then is dissolved in asuitable solvent such as tetrahydrofuran and the like, anddiisobutylaluminium hydride is added dropwise under cooling toselectively reduce carbonyl at 4-position. Further, a protecting groupsuch as triphenylmethyl group and the like is removed with an acid suchas dilute sulfuric acid to give an end compound [I]. In addition, acompound at each reaction step can be purified by silica gel columnchromatography and the like, if necessary.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following Examples illustrate the present invention in detail.

EXAMPLE 1 Synthesis of 2-butyl-1-(4-iodobenzyl)imidazol-4,5-dicarboxylicacid represented by the chemical formula ##STR9##

Dimethyl 2-butylimidazol-4,5-dicarboxylic acid (7.12 g, 29.6 mmol) and4-iodobenzyl bromide (10.56 g, 35.5 mmol) were dissolved in DMF (50 ml),and 60% oily sodium hydride (1.3 g, 32.5 mmol) was added in smallportions while stirring at room temperature. The reaction solution wasstirred at room temperature for 2 hours and methanol was added to treatexcess sodium hydride. Then the reaction solution was neutralized with2N HCl and the product was extracted with dichloromethane. The extractedsolution was dried over sodium sulfate and concentrated in reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:1) to give the titled compound (11.1 g, 82%) asa tan solid (mp:98-99° C., Rf:0.60 silica gel-ethylacetate/hexane/=1/1). This has the following NMR spectrum.

¹ H-NMR (CDCl₃) δ ppm: 0.88 (3H, t, J=7.4 Hz), 1.34 (2H. sex, J=7.4 Hz),1.66 (2H, qui, J=7.4 Hz), 2.63 (2H, t, J=7.4 Hz), 3.81 (3H, s), 3.92(3H, s), 5.35 (2H, s), 6.74 (2H, d, J=8.6 Hz), 7.64 (2H, d, J=8.6 Hz)

EXAMPLE 2 Synthesis of2-butyl-1-(4-iodobenzyl)imidazo[4,5-d]pyridazine-4,(5H),7,(6H)-dionerepresented by the chemical formula ##STR10##

A mixture of dimethyl 2-butyl-1-(4-iodobenzyl)imidazol-4,5-dicarboxylicacid (8.68 g, 19.0 mmol) and hydrazine monohydrate (20 ml) was heated atreflux for 1.5 hours. Excess hydrazine was distilled off under reducedpressure, water (40 ml) was added thereto, the reaction solution wasmade acidic (pH=1) by addition of 12 N HCl and the solution was cooledon ice. The resulting precipitates were filtered, washed successivelywith ethanol (40 ml×2) and ether (40 ml×2), the filtered material wasdried at 50° C. under vacuum to give a titled compound (8.4 g, 100%) aswhite powders (mp>250° C., Rf: 0.58 silicagel-chloroform/methanol=10/1). This has the following NMR spectrum.

¹ H-NMR (DMSO-d₆) δ ppm: 0.86 (3H, t, J=7.5 Hz), 1.33 (2H, sex, J=7.5Hz), 1.66 (2H, qui, J=7.5 Hz), 2.70 (2H, t, J=7.5 Hz), 5.70 (2H, s),6.97 (2H, d, J=8.4 Hz), 7.66 (2H, d, J=8.4 Hz)

EXAMPLE 3 Synthesis of2-butyl-5,8-dimethyl-5,8-dihydro-5,8-ethano-1-(4-iodobenzyl)-1H-1,3,4a,8a-tetraazacyclopentanaphthalene-4,9-dionerepresented by the chemical formula ##STR11##

2-Butyl-1-(4iodobenzyl)imidazo[4,5-d]pyridazine-4,(5H),7,(6H)-dione(7.64 g, 18.0 mmol) and 1,4dimethyl-1,3-cyclohexanediene (purity 64%,4.6 g, 27.3 mmol) were suspended in dichloromethane (150 ml) and thesuspension was cooled to -25° C. Lead tetraacetate (purity 91%, 26.3 g,54.0 mmol) was added in small portions. The temperature of the reactionmixture was returned slowly to 0° C. to react for 2.5 hours. Toluene(100 ml) was added and the resulting precipitates were filtered andwashed with dichloromethane. The filtrate and washes were combined andconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (ethyl acetate) to give a titledcompound (7.65 g, 80%) as pale-yellow powders (mp: 157-158° C., Rf: 0.51silica gel-ethyl acetate). This has the following NMR spectrum.

¹ H-NMR (CDCl₃) δ ppm: 0.86 (3H, t, J=7.5 Hz), 1.31 (2H, sex, J=7.5 Hz),1.61 (2H, m), 1.69 (2H, qui, J=7.5 Hz), 2.13 (3H, s), 2.21 (3H, s), 2.61(2H, t, J=7.5Hz), 5.59 (2H, AB, JAB=16 Hz), 6.36 (2H, AB, JAB=16 Hz),6.81 (2H, d, J=8.4 Hz), 7.64 (2H, d, J=8.4 Hz)

EXAMPLE 4 Synthesis of2-butyl-5,8-dimethyl-5,8-ethano-1-(4iodobenzyl)-5,6,7,8-tetrahydro-1H-1,3,4a,8a-tetraazacyclopentanaphthalene-4,9-dione

2-Butyl-5,8-dimethyl-5,8-dihydro-5,8-ethano-1-(4iodobenzyl)-1H-1,3,4a,8a-tetraazacyclopentanaphthalene-4,9-dione(3 g, 5.66 mmol) and p-toluenesulfonylhydrazine (8.4 g, 45.1 mmol) weredissolved in DMF (16 ml) and the solution was heated to reflux. Asolution obtained by dissolving sodium acetate (7.4 g, 90.2 mmol) inwater (16 ml) was added dropwise slowly over 3 hours. The solvent wasdistilled off under reduced pressure, the residue was dissolved indichloromethane, washed with water, dried over sodium sulfate andconcentrated under reduced pressure. The residue was washed with hexaneand dried at 45° C. under vacuum to give a titled compound (2.6 g, 87%)as white powders (mp: 208-209° C., Rf: 0.51 silica gel-ethyl acetate).This has the following NMR spectrum.

¹ H-NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=7.5 Hz), 1.33 (2H, sex, J=7.5 Hz),1.61-1.76 (6H, m), 1.81 (3H, s), 1.89 (3H, s), 2.17 (4H, m), 2.64 (2H,t, J=7.5 Hz), 5.61 (2H, s) 6.83 (2H, d, J=7.1 Hz), 7.65 (2H, d, J=7.1Hz)

EXAMPLE 5 Synthesis of2-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)-4biphenyl]methyl]-1H-1,3,4a,8a-tetraazacyclopentanaphthalene-4,9-dionerepresented by the chemical formula

4Phenyl-1-triphenylmethyl-1H-tetrazole (365 mg, 0.94 mmol) was dissolvedin THF (2 ml), the solution was cooled to -20° C. and a 1.6 M solutionof n-butyl lithium in hexane (0.7 ml, 1.12 mmol) was added dropwisewhile stirring under nitrogen atmosphere. The temperature of thissolution was raised from -20° C. to -10° C. over 1 hour and the solutionwas stirred for a further 30 minutes. A suspension of zinc chloride (153mg, 1.12 mmol) in THF (1 ml) was added thereto and the reaction waswarmed to 0° C. to give arylzinc chloride.

In a separate vessel, bis(triphenylphosphine)nickel (II) dichloride(62.9 mg, 0.096 mmol) was suspended in THF (1 ml) under nitrogenatmosphere, and a 1M solution of methylmagnesium chloride in THF (0.2ml, 0.2 mmol) was added thereto at room temperature. Then a solution of2-butyl-5,8-dimethyl-5,8-ethano-1-(iodobenzyl)-5,6,7,8-tetrahydro-1H-1,3,4a,8a-tetraazacyclopentanaphthalene-4,9-dione(250 mg, 0.47 mmol) in THF (6 ml) and a solution of arylzinc chloride inTHF as prepared above were added thereto successively. The reactionmixture was stirred at room temperature for 10 hours, acetic acid (0.2ml) was added to stir for 30 minutes, a saturated aqueous solution ofsodium chloride (2 ml) was added to stir for another 30 minutes, and themixture was allowed to stand to separate THF layer and aqueous layer.The THF layer was taken, the aqueous layer was extracted with THF (5ml), the THF layers were combined, washed with 28% ammonia solution inwater (3 ml), dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give a titled compound (289 mg, 77.4%) as white powders.

EXAMPLE 6 Synthesis of2-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)-4-biphenyl]methyl]-1H,4H-1,3,4a,8a-tetraazacyclopentanaphthalene-9-onerepresented by the chemical formula ##STR12##

2-Butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)-4biphenyl]methyl]-1H-1,3,4a,8a-tetraazacyclopentanaphthalene-4,9-dione(93,1 g, 0.12 mmol) was dissolved in THF (1.2 l) while warming, thesolution was cooled to -45° C., and a solution of DIBAH (1.5 M solutionin toluene, 230 ml, 0.35 mol) was slowly added dropwise under nitrogenatmosphere. The mixture was stirred at the same temperature for 1 hour,a saturated aqueous solution of sodium chloride was added and themixture was warmed to room temperature. The organic layer was decanted,the precipitates were washed with ethyl acetate, combined with the aboveorganic layer and the mixture was dried over sodium sulfate. The solventwas distilled off under reduced pressure to give a titled compound (96.6g) as pale yellow solid. This has the following NMR spectrum.

¹ H-NMR (CDCl₃) δ ppm: 0.82 (3H, t, J=7.2 Hz), 1.14 (3H, s), 1.20-1.31(2H, m),149-168 (6H, m), 1.71 (3H, s), 2.04-2.14 (4H, m), 2.43 (2H, t,J=8.0 Hz), 3.98 (2H, s), 5.46 (2 H, s) 6.89-7.51 (22H, m), 7.88 (1H, dd,J=1.5, 7.5 Hz)

EXAMPLE 7 Synthesis of2-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-1-[[2'-(1H-tetrazol-5-yl)-4biphenyl]methyl]-1H,4H-1,3,4a,8a-tetraazacyclopentanaphthalene-9-onerepresented by the chemical formula ##STR13##

2-Butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)-4-biphenyl]methyl]-1H,4H-1,3,4a,8a-tetraazacyclopentanaphthalene-9-one(96.3 g) was dissolved in acetone (720 ml), 2N HCl (220 ml) was addedthereto and the mixture was heated to stir at 55° C. for 30 minutes. Thereaction mixture was cooled to 0° C., a saturated aqueous solution ofsodium chloride was added to adjust to pH 4, acetone was distilled offunder reduced pressure and the resulting aqueous layer was extractedwith methylene chloride. The organic layer was washed successively withwater and saturated aqueous solution of sodium chloride and dried oversodium sulfate. The solvent was distilled off under reduced pressure,the resulting residue was purified by silica gel column chromatography(chloroform-chloroform/methanol=50/1) to give a titled compound (53.5 g,91%, 2st eps) as pale yellow solid. This has the following NMR spectrum.

¹ H-NMR (CDCl₃) δ ppm: 0.84 (3H, t, J=7.2 Hz), 1.01 (3H, s), 1.22-1.36(2H, m), 151-1.69 (6H, m), 1.58 (3H, s), 1.89-2.01 (4H, m), 2.41 (2H, t,J=7.7 Hz), 3.63 (2H, s), 5.43 (2H, s), 6.91 (2H, d, J=8.0 Hz), 7.05 (2H,d, J=8.0 Hz), 7.44-7.65 (3H, m), 7.87 (1H, d, J=6.8 Hz)

We claim:
 1. A process for producing a compound represented by thechemical formula: ##STR14## or a pharmacologically acceptable saltthereof which comprises: reacting a compound represented by the chemicalformula: ##STR15## with 4-iodobenzyl or 4-bromobenzyl-bromide andsubsequently with hydrazine to give a compound represented by thechemical formula: ##STR16## wherein X represents bromine or iodine,reacting the above compound with 1,4-dimethyl-1,3-cyclohexanediene inthe presence of lead tetra-acetate,subjecting the newly generated doublebond of the formula: ##STR17## to catalytic or diimide reduction andsubsequently to diisobutylaluminium hydride reduction to give a compoundrepresented by the chemical formula: ##STR18## wherein X representsbromine or iodine, and reacting the above compound with a compoundrepresented by the general formula: ##STR19## wherein R representshydrogen, sodium, potassium, alkyl group or optionally substituted arylgroup and when R is other than hydrogen removal of R groups to give##STR20##
 2. A process for producing a compound represented by thechemical formula: or a pharmacologically acceptable salt thereof whichcomprises:reacting a compound represented by the chemical formula:##STR21## with 4-iodo benzyl or 4-bromobenzyl bromide and subsequentlywith hydrazine to give a compound represented by the chemical formula:##STR22## wherein X represents bromine or iodine, reacting the abovecompound with 1,4-dimethyl-1,3-cyclohexanediene in the presence of leadtetra-acetate, subjecting the newly generated double bond of theformula: ##STR23## to catalytic or diimide reduction to give a compoundrepresented by the chemical formula: ##STR24## wherein X representsbromine or iodine, reacting the above compound with a compoundrepresented by the chemical formula: ##STR25## wherein R representshydrogen, sodium, potassium, alkyl group or optionally substituted arylgroup, and subjecting the resulting compound to diisobutylaluminiumhydride reduction and when R is other than hydrogen removal of R groupsto give ##STR26##